herpes
Broad-spectrum antiherpes activities of 4-hydroxyquinoline carboxamides, a novel class of herpes virus polymerase inhibitors.

Oien NL, Brideau RJ, Hopkins TA, Wieber JL, Knechtel ML, Shelly JA, Anstadt RA, Wells PA, Poorman RA, Huang A, Vaillancourt VA, Clayton TL, Tucker JA, Wathen MW.

Discovery Research, Pharmacia Corp., Kalamazoo, Michigan 49001, USA.

Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human alpha, delta, and gamma polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpes viruses. However, these compounds were not active against several nonherpes viruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpes viruses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850254&dopt=Abstract herpes medicine



herpes
Analysis of nucleotide sequence variations in herpes simplex virus types 1 and 2, and varicella-zoster virus.

Chiba A, Suzutani T, Saijo M, Koyano S, Azuma M.

Department of Microbiology, Asahikawa Medical College, Japan.

To analyze the difference in the degree of divergence between genes from identical herpes virus species, we examined the nucleotide sequence of genes from the herpes simplex virus type 1 (HSV-1) strains VR-3 and 17 encoding thymidine kinase (TK), deoxyribonuclease (DNase), protein kinase (PK; UL13) and virion-associated host shutoff (vhs) protein (UL41). The frequency of nucleotide substitutions per 1 kb in TK gene was 2.5 to 4.3 times higher than those in the other three genes. To prove that the polymorphism of HSV-1 TK gene is common characteristic of herpes virus TK genes, we compared the diversity of TK genes among eight HSV-1, six herpes simplex virus type 2 (HSV-2) and seven varicella-zoster virus (VZV) strains. The average frequency of nucleotide substitutions per 1 kb in the TK gene of HSV-1 strains was 4-fold higher than that in the TK gene of HSV-2 strains. The VZV TK gene was highly conserved and only two nucleotide changes were evident in VZV strains. However, the rate of nonsynonymous substitutions in total nucleotide substitutions was similar among the TK genes of the three viruses. This result indicated that the mutational rates differed, but there were no significant differences in selective pressure. We conclude that HSV-1 TK gene is highly diverged and analysis of variations in the gene is a useful approach for understanding the molecular evolution of HSV-1 in a short period.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10358747&dopt=Abstract herpes medicine



herpes
Immunization against genital herpes with a vaccine virus that has defects in productive and latent infection.

Da Costa XJ, Jones CA, Knipe DM.

Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

An effective vaccine for genital herpes has been difficult to achieve because of the limited efficacy of subunit vaccines and the safety concerns about live viruses. As an alternative approach, mutant herpes simplex virus strains that are replication-defective can induce protective immunity. To increase the level of safety and to prove that replication was not needed for immunization, we constructed a mutant herpes simplex virus 2 strain containing two deletion mutations, each of which eliminated viral replication. The double-mutant virus induces protective immunity that can reduce acute viral shedding and latent infection in a mouse genital model, but importantly, the double-mutant virus shows a phenotypic defect in latent infection. This herpes vaccine strain, which is immunogenic but has defects in both productive and latent infection, provides a paradigm for the design of vaccines and vaccine vectors for other sexually transmitted diseases, such as AIDS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10359827&dopt=Abstract herpes medicine



herpes
Identification and structure of the Marek's disease virus serotype 2 glycoprotein M gene: comparison with glycoprotein M genes of Herpesviridae family.

Cai JS, Jang HK, Izumiya Y, Tsushima Y, Kato K, Damiani AM, Miyazawa T, Kai C, Takahashi E, Mikami T.

Department of Veterinary Microbiology, Graduate School of Agriculture and Agricultural Life Science, The University of Tokyo, Japan.

We determined the nucleotide sequence of a portion of BamHI-C fragment of Marek's disease virus serotype 2 (MDV2) strain HPRS24 which was suspected to contain the homologue of the herpes simplex virus type 1 (HSV-1) gene UL10, encoding glycoprotein M (gM). An open reading frame whose translation product exhibited significant similarities to HSV-1 gM protein and respective proteins of other herpes viruses of 37.5% and 45.5% to 31.8%, respectively, was identified. A number of distinct transcriptional consensus sequences were found upstream of the first putative start codon of MDV2 UL10 protein. In transcriptional analysis, the gene was transcribed into an 1.5 kb RNA. The primary translation product comprises 424 amino acids with a predicted molecular weight of 46.9 kDa. The predicted MDV2 UL10 protein contains eight hydrophobic domains with sufficient length and hydrophobicity to span the lipid bilayer conserved in the genomes of all herpes viruses which have been sequenced so far. In the region located between the first and second hydrophobic domains, two potential N-linked glycosylation sites were presented. Interestingly, highly charged residues were abundantly possessed in the carboxy-terminal part of the MDV2 UL10 protein. By comparison of the amino acid sequence of the MDV2 UL10 gene with the homologues from other herpes viruses, the data might contribute for further evidence of the evolution of herpes viruses from a common progenitor and an ancient example of MDV2 belonging to the Alphaherpesvirinae subfamily. In addition, the existence of corresponding genes in human, mammalian, and avian herpes virus genomes, suggests indirectly an important role for gM in the natural life cycle of the virus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10379942&dopt=Abstract herpes medicine



herpes
Pain and somatosensory dysfunction in acute herpes zoster.

Haanpaa M, Laippala P, Nurmikko T.

Department of Neurology, Tampere University Hospital, Finland.

OBJECTIVE: To determine the nature of sensory change and its association with pain and allodynia in acute herpes zoster. DESIGN: Prospective clinical study. PATIENTS: One hundred thirteen immunocompetent patients with acute herpes zoster. METHODS: Onset, intensity, and quality of pain and severity of rash were recorded. Quantitative somatosensory testing for tactile and thermal thresholds, qualitative pinprick testing, and testing of dynamic and static allodynia were performed within the affected dermatome, its mirror-image dermatome, and in an adjacent dermatome bilaterally. RESULTS: Acute pain was reported as severe in 50%, moderate in 29%, mild in 12%, and absent in 9% of patients. Preherpetic pain (median = 4 days, range = 1-60 days) was experienced by 71%. Mechanical allodynia, dynamic, static, or both, was found in 37% of patients and was noted to extend one or more dermatomes outside the rash in 12%. In the affected dermatomes, thresholds were elevated for warmth and cold, lowered for heat pain, and unchanged for touch when compared with the contralateral side. Logistic regression analyses showed that compression-evoked allodynia, brush-evoked allodynia, and the history of preherpetic pain were more frequently encountered in patients with severe pain. Sensory threshold changes were not associated with the severity of pain or rash or with the presence of allodynia. CONCLUSION: Pain, allodynia, and altered sensation are common features of acute herpes zoster. They are likely to result primarily from widespread neural inflammation within the affected afferent system. The sensory changes found in acute herpes zoster are different from those reported in published studies on postherpetic neuralgia and suggest sensitization phenomena and preservation of tactile functions rather than major neural damage. The exact mechanisms for acute herpes zoster pain, however, remain speculative.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10382920&dopt=Abstract herpes medicine



herpes
Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time.

Benedetti JK, Zeh J, Corey L.

University of Washington, Department of Biostatistics, Seattle 98195, USA.

BACKGROUND: Visits to physicians for genital herpes simplex virus (HSV) infection continue to increase. Most patients with symptomatic infections have recurrences, but no studies of the long-term clinical course of genital herpes are available. OBJECTIVE: To determine whether the frequency of HSV recurrences decreases over time. DESIGN: Observational cohort study. SETTING: University-based research clinic. PATIENTS: 664 persons with genital herpes followed for at least 14 months. MEASUREMENTS: Patients were classified as having initial or recurrent HSV-1 or HSV-2 infection. Patient-reported recurrences and observed recurrences were recorded in a database; more than 12,000 recurrences were analyzed. RESULTS: Median recurrence rates in the first year of follow-up were one and five per year in patients with newly acquired HSV-1 and HSV-2 infection, respectively; second-year rates were significantly lower in both groups. Patients presenting with recurrent HSV-2 infection had higher rates of recurrence in the first and second years and no significant decrease; significant decreases were detected with longer follow-up. One third of all patients experienced a decrease of two or more recurrences per year between years 1 and 2. Patients infected with HSV-2 who were followed for more than 4 years had a median decrease of two recurrences between years 1 and 5. However, 25% of these patients had an increase of at least one recurrence in year 5, illustrating the variability among HSV-infected persons. Decreases over time among patients who never received suppressive therapy were similar to decreases during untreated periods in patients who received suppressive therapy. CONCLUSIONS: Herpes simplex virus type 2 infection continues to be a chronic remitting illness. Over time, however, clinically significant reductions occur in a majority of patients. Physicians may wish to periodically assess the need for continued treatment with daily suppressive antiviral chemotherapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10391810&dopt=Abstract herpes medicine



herpes
An interactive, computer-based program to educate patients about genital herpes.

Bensen C, Stern J, Skinner E, Beutner K, Conant M, Tyring S, Reitano M, Davis G, Wald A.

School of Nursing, University of Washington, Seattle, USA.

BACKGROUND AND OBJECTIVES: Education and counseling constitute a substantial portion of management of patients with genital herpes. Innovative methods for education about genital herpes are needed. GOAL: To test the ability of an interactive, computer-based program to educate patients about genital herpes. STUDY DESIGN: Persons seeking care at five urban offices were asked to participate. A knowledge test about genital herpes was administered before and after participation. Participants' satisfaction was assessed with a questionnaire. RESULTS: Four hundred thirty-five participants enrolled, and 428 completed the herpes knowledge test. Of six questions evaluated, a statistically significant increase in the proportion of correct answers was noted on five of six questions. Fifty-one percent of participants answered all the questions correctly after the program, compared with 39% before the program. Satisfaction with the program was very high. CONCLUSIONS: Innovative, computer-based programs can provide education and assist in the management of chronic sexually transmitted infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10417026&dopt=Abstract herpes medicine



herpes
Bystander effect of purine nucleoside analogues in HSV-1 tk suicide gene therapy is superior to that of pyrimidine nucleoside analogues.

Degreve B, De Clercq E, Balzarini J.

Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.

Introduction of the herpes simplex virus type 1 thymidine kinase gene into tumor cells, followed by the administration of the antiherpes nucleoside analogue ganciclovir has been demonstrated to be effective in eliminating solid tumors in animals. The success of this combination treatment largely depends on the bystander effect, i.e. the killing of nontransfected tumor cells by activated drug carried over from the nearby herpes thymidine kinase (tk) gene-transfected cells. We evaluated the in vitro bystander effect of several antiherpes purine and pyrimidine nucleoside analogues, using a colorimetric assay. All pyrimidine nucleoside analogues, including (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), showed low, if any, bystander killing effect. In contrast, purine nucleoside analogues, such as ganciclovir, were endowed with a pronounced bystander killer effect. Lobucavir (Cyclobut-G), a ganciclovir analogue, displayed a two- to three-fold more pronounced bystander killer effect than ganciclovir, eliminating, at a concentration of 10 microM, 75% and 90% of a cell population that contained 5% and 10% tk gene-transfected cells, respectively. These findings were corroborated by autoradiographic analysis that showed that 2'-3H-BVDU metabolites formed in the herpes tk gene-transfected tumor cells were much less efficiently incorporated in the DNA of bystander cells than 8-3H-GCV. This indicates that, under the same experimental conditions, BVDU metabolites are less prone to pass the gap junctions than GCV metabolites.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10435100&dopt=Abstract herpes medicine